TY - JOUR
T1 - Blood miR-144-3p
T2 - a novel diagnostic and therapeutic tool for depression
AU - van der Zee, Yentl Y.
AU - Eijssen, Lars M.T.
AU - Mews, Philipp
AU - Ramakrishnan, Aarthi
AU - Alvarez, Kelvin
AU - Lardner, Casey K.
AU - Cates, Hannah M.
AU - Walker, Deena M.
AU - Torres-Berrío, Angélica
AU - Browne, Caleb J.
AU - Cunningham, Ashley
AU - Cathomas, Flurin
AU - Kronman, Hope
AU - Parise, Eric M.
AU - de Nijs, Laurence
AU - Shen, Li
AU - Murrough, James W.
AU - Rutten, Bart P.F.
AU - Nestler, Eric J.
AU - Issler, Orna
N1 - Funding Information:
This work was funded by a grant from Janssen Pharmaceutical Companies, by a grant from the National Institute of Mental Health (R01MH051399 to EJN) and by the Hope for Depression Research Foundation. We wish to thank Drs. Vincent Vialou and Christophe Gerald, previous members of the Mount Sinai research team who worked on the original mouse study.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/11
Y1 - 2022/11
N2 - Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression.
AB - Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression.
UR - http://www.scopus.com/inward/record.url?scp=85135259472&partnerID=8YFLogxK
U2 - 10.1038/s41380-022-01712-6
DO - 10.1038/s41380-022-01712-6
M3 - Article
C2 - 35902629
AN - SCOPUS:85135259472
SN - 1359-4184
VL - 27
SP - 4536
EP - 4549
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 11
ER -